The effect of local therapy on the survival of patients with breast cancer has been debated for decades. Three viewpoints have been proposed on the basis of various hypotheses concerning the biology of breast cancer. Is breast cancer a local disease that spreads predictably over time to develop distant metastases?

Is it a systemic disease from the outset, with distant metastases present well before diagnosis? Or is the truth somewhere in between, with many cancers being localized at diagnosis and, if untreated or recurrent, acquiring the ability to metastasize and kill?

These differing views have vastly different implications for the treatment of patients. Recently, several lines of evidence have emerged that suggest answers to these questions.

Three Theories of Cancer Spread

Throughout the first half of the 20th century, the prevailing theory of the development of distant metastasis in breast cancer was shaped by the thinking of Dr. William Halsted and his disciples. The “Halstedian” theory proposed that breast cancer begins as a strictly local disease and that tumor cells spread over time in a contiguous manner away from the primary site through lymphatics. According to this theory, even distant metastases are the result of direct extensions of local involvement (affecting the breast, the chest wall, axillary and supraclavicular lymph nodes, or any combination of the sites). The Halstedian approach thus dictated that aggressive local therapy for control of disease in the breast, chest wall, and regional lymph nodes would have a substantial effect on survival. His ideas also provided justification for ever more radical breast-cancer surgery.

The “systemic” view arose in reaction to the Halstedian theory, since disease develops at distant sites in many women with breast cancer, even though the primary cancer is well controlled locally with aggressive surgery. On the basis of this information, Dr. Bernard Fisher and others promulgated the view that breast cancer is a systemic disease and that it can be divided into two distinct groups: tumors that have the ability to metastasize to distant sites and those that lack this ability. According to this view, which prevailed in the last half of the 20th century, if distant metastases were destined to develop, such metastases had already occurred at the time of diagnosis of the breast tumor. Because the length of a patient’s overall survival is a function of distant disease, this theory predicted that treatments that improve local control would have little or no effect on overall survival. Instead, the emphasis was on the importance of effective systemic therapy in breast-cancer treatment. Over the past three decades, the development of systemic therapy has indeed been associated with substantial improvements in the overall survival of patients with clinically localized breast cancer. During this time, patients were counseled that the prevention of a local recurrence was of limited importance with regard to survival, since such a recurrence could be treated when it developed, and that the development of a local recurrence would not lead to the development of metastatic disease.

Although it is clear that the Halstedian view is not correct for all breast cancers, it is not clear that the systemic view is entirely correct either. A third hypothesis synthesized aspects of these two opposing approaches. In this view, breast cancer is “a heterogeneous disease . . . [with] a spectrum of proclivities extending from a disease that remains local throughout its course to one that is systemic when first detectable.”  This theory holds that for many breast cancers, there is a time when tumor cells have not metastasized to distant sites but that it is generally not known whether this time has passed at the point of diagnosis for any patient. According to this view, failure to achieve initial local control will allow some tumors to disseminate later to distant sites, reducing a patient’s chance for long-term survival. The spectrum theory acknowledges that the greater the likelihood that systemic spread (now known to occur primarily through direct hematogenous routes) has occurred at the time of diagnosis in a patient, the lower the likelihood that local therapy will influence the patient’s survival.

Evidence from Clinical Trials

Until recently, most evidence from clinical trials seemed to support the systemic view of breast cancer. Randomized trials from the National Surgical Adjuvant Breast and Bowel Project (NSABP), which studied the effect of improving local control by increasing the extent of surgery or adding radiation therapy after total mastectomy (NSABP B-04) or breast-conserving surgery (NSABP B-06), demonstrated similar survival for the different treatment groups despite substantial improvement in local control with additional surgery and radiation therapy. The results from these trials were widely interpreted as providing strong evidence for the systemic theory. However, in these trials, there were insufficient events (in this case, deaths) to detect small, but clinically important, differences in overall mortality.

Evidence has emerged that casts doubt on the validity of the systemic theory for all patients with breast cancer. First, there is evidence that mammographic screening reduces breast-cancer mortality. The summary findings from a meta-analysis of randomized studies of mammographic screening demonstrated that in screened populations, the relative risk of death from breast cancer was significantly reduced (relative risk, 0.85; 95% confidence interval [CI], 0.73 to 0.99), as compared with that in unscreened populations. Between 1990 and 2003, the rate of death from breast cancer among women of all ages, adjusted to the 2000 population, fell from 33.1 to 25.2 per 100,000 women, a decrease of 24%. It is estimated that about half of this reduction can be attributed to the increased use of screening mammography.

Thus, in some patients, earlier diagnosis (with screening) can prevent the development of distant metastases. The reduction in mortality with earlier diagnosis strongly suggests that the likelihood of distant dissemination of the cancer can be influenced by the timing of the diagnosis. If the systemic theory were completely correct, early detection would have little effect on breast-cancer mortality. The fact that screening decreases mortality implies that at least some breast cancers develop the propensity to spread distantly over time and suggests that strict classification of breast cancers according to the systemic theory as either having or not having metastatic potential is not possible.

Second, there is mounting evidence from randomized clinical trials supporting a link between local control and overall survival in breast cancer. One such link was discovered from studying the addition of radiation therapy after mastectomy and adjuvant systemic therapy in women with breast cancer at high risk for local recurrence. Randomized trials have shown not only decreased local recurrences with radiation therapy but also an improvement in overall survival for both premenopausal and postmenopausal women.

Finally, because a single randomized study may not have the statistical power to detect small, but clinically meaningful, differences in survival, pooled analyses or meta-analyses of randomized trials have been undertaken to investigate the relationship between local control and mortality in breast cancer. A recent study by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) presented the findings from 78 randomized clinical trials evaluating the extent of surgery and the use of radiation therapy. This report analyzed data from 42,000 patients with breast cancer who had been treated in trials beginning before 1995 and examined more extensive versus less extensive surgery, radiation therapy versus no radiation therapy, and extensive surgery versus radiation therapy.

Future Directions

The recognition of the influence of local control on survival not only has important implications for treatment decisions today but also should influence our approach to clinical and translational research in the years to come. Since more effective local control can be beneficial only in patients at risk for local recurrence, there is a need to identify more robust predictors of local recurrence. Gene-expression analyses have been used to identify patients at increased risk for distant recurrence. There is also the suggestion that expression profiling may be helpful in identifying patients at greater risk for local recurrence. We will need to gain a better understanding of the interplay between tumor biology, the anatomic extent of disease, and the risk of local recurrence. At the same time, it will be important to determine whether the risk reduction from improved local therapy varies across molecular subtypes of breast cancer. Breast-cancer care is a multidisciplinary endeavor, and progress in treatment will also require multidisciplinary research efforts that carefully consider the importance of local control.

Rinaa S. Punglia, M.D., M.P.H., Monica Morrow, M.D., Eric P. Winer, M.D., and Jay R. Harris, M.D.

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